DNA Methylation and the Cancer Epigenome Biological and Translations Implications

Stephen B. Baylin, M.D., is deputy director of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Virginia and D.K. Ludwig professor of oncology and medicine. He is chief of the Cancer Biology Division and associate director for research of the center.

Abstract

Genome-wide mapping studies are dramatically contributing to remarkable increases in our understanding of epigenetic abnormalities in cancer. Abnormal DNA methylation, both losses and gains, and key associated chromatin changes may largely affect distinct genomic regions which contain nuclear lamin associated, late replicating DNA , enriched for low transcription, developmental, genes with promoter region, “bivalent” chromatin . Such chromatin, in embryonic and adult stem cells, is essential for maintenance of the stem cell state. Furthermore, in multiple tumor types, frequent mutations are being found in genes which control normal epigenomes. While the phenotypic consequences of these largely remain to be dissected, mutations in the IDH1 and 2 genes, and in the Tet family of proteins which trigger steps for active DNA de-methylation, are now linked to DNA methylation and chromatin alterations associated with abnormal gene silencing. Importantly, multiple of the above epigenetic abnormalities are being found in cancer-risk states which involve chronic inflammation and attendant increases in reactive oxygen species (ROS). Finally, all of the above biology has exciting translational implications for the concepts of “epigenetic therapy” for cancer and molecular signatures which can guide such treatments and also be useful for cancer diagnosis and staging.

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